Arsenical compound.



M. D., residing at Flushing, in

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nasonar.

No Drawing.

Specification of Letters Patent. Patented Sept. 24:, 1918.,

Application filed October a, 1917. Serial No. 194,461.

To all whom it may concern:

Be it known that we, WALTER A. JAcoBs, Ph. D., residing at Mount Vernon, Westchester county, New York, WADE H. BROWN,

the city of borough of Queens, Queens county, New York, MICHAEL HEIDELBERGER, Ph. D.,.residing in the city of New York, borough of Manhattan, county and State of New York, and Louise PEARCE, M. 1)., residing inthe city of New York, borou h. of Manhattan, county and State of New ork, all citizens of the United States, have jointly invented a new and Improved Arsenical Compound, of which the following is a specification.

In our co-pending application, Serial No. 194,459, we have described a class of arsenical compounds of use in the treatment of trypanosggnal or spirochaetal infections, which may be "described as an aromatic arsenic acid possessing an oa-aminoacylamin side chain NHCHR.CONRR, in which R may be alkyl, aryl or hydrogen and R and R" may be alkyl or hydrogen, the aromatic nucleus being joined to the oc-amino group in said side chain, and especially pointed out the value of the substance N-phenylglycinamid-p arsonic acid. We have further found, as set forth in this application, that a new class of arsenicals, important for the treatment of trypanosomiasis or spirochaetal infections, is obtained when R or R" is made to represent an aryl group such as phenyl, tolyl, etc, or their halogen, nitro, amino, hydroxy, alkoxy (which may. include the UCH CUUH, OCT-LEONE, or Utili CUNHCONH, group), carboxy, carbonamid, carboxureid, sulfonic acid, sulfonamid,

ortho, meta, or para position to the amid group. This group may occur several times or in combination with other groups on the same benzene nucleus. In the nucleus containing the arsonic acid (AsO,H,) group, the arsenic acid groupmay also be in the ortho or meta position. and may also be accompanied by other substituting groups, as described in the aforesaid co-pending application. Likewise, the NHGH CQNH chain joining the two aromatic nuclei may be changed to a homologue such as NHCHRoQNH, in which R may be alkyl or aryl, as described in our co-pending application, Serial No. 194459.

These substances, as arsenic acids, readily dissolve in equivalent amounts of dilute alkali and carbonates to form neutral and stable solutions, from which they are, as a rule, precipitated by acetic acid or mineral acids.

These substances were prepared by the reaction of the aminophenyl-arsonic acid or its homologues or isomers with e-halogenacyl aromatic amino compounds in aqueous or dilute ethyl or methyl alcoholic or dilute acetone solution. In the case of the simpler amines, heating of the phenylglycin ester arsonie acid with the amins either alone or in a solvent yielded the desired compound. The following examples will demonstrate the method of preparing these substances. Many of them have not only afforded good therapeutic results but form the basis for the synthesis of other substances with still more valuable therapeutic properties.

Example l-1l7 (Filmy l p glycmamlzd.

New York,

- masonic acid) co acylammo, uramino and other substitution grams of phenyl lycin methyl ester-pproducts. Such substituting groups were 'arsonic acid are mixed with 120 gm. anilin used alone and in combination as polysuhand 120 gm. methyl alcohol, and the mixture stituted aryl compounds. The following heated in the water bath until solution is formula complete. The methyl alcohol is allowed to boil 0d and the residue heated for 6 hours.

On cooling, the cr 'stalline mass is dissolved in an excess of di ute sodium hydroxld and then an excess of acetic acid is added. The

phenylgl cinanilid-p-arsonic acid separates x as a co orless microcrystalline substance.

This, after filtration, is redissolved in dllute i ammonia and reprecipitated with acetic acid.

The product so obtamed is pure. It forms represents thetype here presented, in which minute needles which do not melt below at X lap in the sec o. a

represts; any substituting till) Ewample H[V (ram 2; --'p (WSW/226 acid) gZg cinam'ZicZ. i

43A grams of p-aminophnylarsonic acid are dissolved in 200 cc. normal sodium hydroxid solution and treated With 52 grams Ewamplc Ill-N- (PhenyZ-p-arsom'c acid) glycyZ-mcmz'nophenol.

143 grams p-aminophenyl arsonic acid are dissolved in 660 cc. of normal sodium hydroxid solution or a solution or suspension of any other suitable basic substance, and 122 gramsm-chloroacetylaminophenol added. The mixture is brought to a boil. After a short time the reaction product separates in lustrous crystals. The mixture is heated in all for one hour. On cooling it is filtered, Washed with Water, and ice-crystallized by dissolving in dilute ammonia or alkali and reprecipitating With acetic acid. It forms minute platelets Which decompose above 230 C.

The foregoing are a few examples of substances falling within the spirit and scope of our invention. It will be obvious to anyree -lei one skilled in the art that many variations in the exact constitution of the substances described may he made Without departing rrtm the spirit and scope of our invention.

@The sodium salts of the compounds are obtained in the usual Way and are especially recommended for use.

What We claim is:

1. As a new product, an aromatic arsonic acid having in its molecule an oc-amino-acylarylamin side chain, the aromatic nucleus containing the arsenic being joined to the oc-amino group in said side chain, the acyl radical of said side chain containing a plurality of carbon atoms. I

2. As a new product, an aromatic arsonic acid having in its molecule an c-amino-acylarylamin s1de chain having the general formulaNHCHRC ONHAr, in Which R is allryl or aryl or hydrogen and Ar is an arcmatic radical.

3. As a new product, an N- (aryl arsonic .acid) -glycylo2ryaryl amin. I A. As a new "product, an N-(phenyl Jarsonicacid) -glycylaminophenol. a

5. As a new product, N- (phenyl-p-arsonlc acid) --glycyl-m-aminophenol o As on HCH OOI II-I WALTER A. JACOBS, PH. D. WADE ll. BROWN, Ill. l). Mllllll: HEIDELBERGEE, lPH. ll. LOUISE PEARCE, M. D. 

